I Introduction:
Drug hypersensitivity reactions (DHR) are immune or inflammatory reactions elicited by a small molecule and occasionally proteins etc.. DHR can be sub-classified as a specific immune reaction against the drug acting as antigen with drug-specific stimulations of antibodies or T-cells (drug allergy ), as off-target p harmacological activity of drugs with i mmune receptors (human leukocyte antigens, HLA or T cell receptor for antigen, TCR) leading to T-cell mediated immune stimulations (p-i-concept ) and as pseudo-allergic reactions where the drug therapy results in activation of inflammatory cells or mediators without the involvement of the specific immune system (“pseudo-allergy ”) (1 ).
The clinical picture of DHR is very heterogeneous as different cell types (T-cells, mast cells (MC), basophils, eosinophils, neutrophils, etc) and inflammations are involved (2,3,4). This report focusses on IgE-mediated adverse reactions to small molecules, normally <1000 D. They represent an uncommon, but potentially dangerous complication of drug therapy. Symptoms appear rapidly after drug exposure and include generalized urticaria, angioedema, bronchospasm and anaphylaxis with respiratory and/or gastrointestinal symptoms, cardiac arrest and even death. Indeed, drug elicited anaphylaxis is considered to be particularly dangerous with a high rate of deadly outcomes (5).
The underlying mechanism of IgE-mediated drug allergy is based on the hapten concept. It was developed more than 80 years ago by K Landsteiner and others, stating that small molecules like drugs or other chemicals are too small to function as antigen for the immune system (6). Only if the drug acts as a “hapten” and binds to a protein and thus forms a larger drug-protein adduct, it functions as antigen to which immune reactions, including IgE, may develop. This hapten-protein (or hapten-carrier) concept relies on the ability of the drug (or metabolite) to bind via covalent bonds stably to a protein. The immunity may persist for years after stopping therapy. Importantly, the potentially severe symptoms mentioned above do not happen during the sensitization and only may become apparent through a new exposure/re-challenge.
This hapten-carrier concept was validated in an endless number of experiments. It was used to investigate immunity in animal models of autoimmunity, cancer immunology, allergy, and specific immunity to small molecules, etc.. It also served as an explanation for IgE-mediated drug allergy in the clinic: For example, allergy and clinical manifestations after beta-lactam therapy were explained by the hapten-carrier concept (7).
Since only haptens were considered as potential elicitors of drug allergy, drugs in development were assessed for their ability to covalently bind to proteins (8, 9). To reduce the risk for DHR only the development of drugs not capable of forming covalent bonds with proteins was pursued. Nevertheless, drug-induced allergy and in particular IgE-mediated anaphylaxis remained a substantial clinical problem. Anaphylaxis to beta-lactams, to proton-pump inhibitors (PPI), to neuromuscular blocking drugs (NMBA), to disinfectants like chlorhexidine, to radiocontrast media (RCM) and many more still occurs (2, 7, 10-11). Additionally, other ways of mast cell stimulation and degranulation by drugs were recently described, such as reactions triggered by mast cell-specific G protein-coupled receptors (MCGPR) (12).
A critical evaluation of patients with IgE-mediated allergy/anaphylaxis to drugs reveals some inconsistencies in the prevailing concepts, in particular regarding the symptoms during re-challenges: many of the drugs causing anaphylaxis are per se not haptens, but inert chemicals, not able to form covalent bonds; some might have acquired hapten characteristics by metabolism (e.g. sulfamethoxazole, 13). Most importantly, some of the reactions occur very fast before covalent binding or metabolism can occur. Of note as well, the immediate reaction in skin tests or a positive in-vitro basophil activation test (BAT) to an inert drug can not be explained by the hapten-concept. The involved drugs are not “haptens” - leaving open how cross-linking of specific IgE, MC degranulation, and symptoms of IgE-mediated reactions are elicited by the drug (1).
This paper addresses some of these inconsistencies comparing clinical observations to accepted features of IgE-mediated reactions. Such observations comprise the rapidity of the appearance of symptoms, in- vitro and in-vivo diagnosis of drug allergy, experience with desensitizations, pharmaceutical features of drugs and speed of covalent vs non-covalent drug binding to proteins. The result is a new interpretation of IgE mediated drug allergy : It extends the hapten concept and postulates: i) When IgE is induced, the antigen simultaneously induce an MC-unresponsiveness. ii) Some non-covalent bindings of drugs to proteins are affine enough to allow IgE cross-linking by the formed complexes; iii) the formation of covalent hapten-protein adducts in vivo is slow and may allow MC-unresponsiveness both during sensitization and even during re-exposure: No symptoms occur.
The new concept is radical as covalent hapten-protein adducts are considered to be “good” (controlled) antigens, which, although they induce an unwished immunity, do simultaneously induce MC-unresponsiveness; In contrast, non-covalent drug-protein complexes are taking the role of “fake antigens” responsible for harmful effects. The consequences of this new interpretation are potentially wide-reaching both for IgE-mediated drug allergy but also for IgE reactions and symptoms in general.